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DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international,
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Merimepodib, an orally administered small molecule inhibitor of the enzyme inosine 5′-monophosphate dehydrogenase (IMPDH), has completed a phase II clinical trial at Vertex in combination with pegylated interferon and ribavirin for the treatment of hepatitis C viral (HCV).

Merimepodib, also known as VX-497, is orally bioavailable IMPDH inhibitor, which inhibits the proliferation of primary human, mouse, rat, and dog lymphocytes at concentrations of approximately 100 nM. In vivo, oral administration of VX-497 inhibits the primary IgM antibody response in a dose-dependent manner, with an ED(50) value of approximately 30-35 mg/kg in mice. Single daily dosing of VX-497 is observed to be as effective as twice-daily dosing in this model of immune activation. These studies demonstrate that VX-497 is a potent, specific, and reversible IMPDH inhibitor that selectively inhibits lymphocyte proliferation.

IMPDH inhibition leads to a reduction in intracellular guanosine triphosphate (GTP), a cellular molecule required by viruses for replication. Reports indicate that IMPDH inhibitors may enhance the antiviral activity of ribavirin in vitro by depleting GTP and increasing the rate of incorporation of ribavirin into viral RNA, rendering the virus nonfunctional.

EP 0902782; US 5807876; US 6054472; WO 9740028

The oxidation of 3-methoxy-4-methylnitrobenzene (I) with CrO3, H2SO4 and AC2O in acetic acid gives the gem-diacetate (II), which is hydrolyzed with HCl in refluxing dioxane to yield 2-methoxy-4-nitrobenzaldehyde (III). Cyclization of (III) with tosylmethyl isocyanide and K2CO3 in refluxing methanol affords 3-methoxy-4-(5-oxazolyl)nitrobenzene (IV), which is reduced with H2 over Pd/C in ethyl acetate to provide the corresponding aniline (V). The activation of (V) with carbonyldiimidazole (CDI) in THF gives the carboxamide (VI), which is condensed with 3-(tert-butoxycarbonylaminomethyl)aniline (VII), obtained by reaction of 3-aminobenzylamine with Boc2O, and DMAP in refluxing THF to yield the urea (IX). Deprotection of (IX) with TFA in dichloromethane affords the free benzylamine (X), which is finally condensed with the 3-furyl ester of the succinimidyl-activated carbonate (XI) by means of TEA in dichloromethane/DMF.

A suspension of 113 (from Example 5) (250mg, 5.76mmol) in CH2CI2 (lrtiL) was treated in a dropwise fashion at ambient temperature with several equivalents of trifluoroacetic acid and stirred for 90mm. The resulting solution was stripped m vacuo and tritrated with CH2CI2 and methanol. Pure product 168 was isolated by filtration in a yield of 258mg (99%) . The -H NMR was consistent with that of the desired product,

(120)

A suspension of 168 (250mg, 0.55mmol) in 21mL of CH2CI2/DMF (20:1 by volume) was treated with tπethyl amme (193μL, 1.38mmol) and stirred at ambient temperature until homogeneity was reached. The solution was cooled to 0 C, treated with (S) 3- tetrahydrofuranyl-N-oxysuccιnιmιdyl carbonate (635mg, 0.608mmol) and allowed to stir overnight with warming to ambient temperature. The mixture was poured into ethyl acetate (500mL), washed with NaHC0 (aq) ( 2x) , water (2x) , and brme(lx), dried over Na2S04 and stripped m vacuo . Pure product 120 was isolated by tπtration (30mL CH2C12, lOO L ether) in a yield of

212mg (85%) . The *H NMR was consistent with that of the desired product.

The desired intermediate 5-(2-methoxy-4-nitrophenyl)oxazole (IV) has been obtained as follows. The carbonylation of 2-methoxy-4-nitrophenyldiazonium tetrafluoroborate (I) by means of carbon monoxide catalyzed by Pd(OAc)2 and Tes-H in ethyl ether/acetonitrile gives 2-methoxy-4-nitrobenzaldehyde (II), which is cyclized with tosylmethyl isocyanate (III) by means of K2CO3 in refluxing methanol to afford the target intermediate 5-(2-methoxy-4-nitrophenyl)oxazole (IV) (see scheme no. 24362801a, intermediate (IV)).

Charged 15 g of (S) -tetrahydrofuran-3-yl 3- nitrobenzylcarbamate 2c in 120 ml EtOAc to a IL Parr bomb at room temperature under a blanket of N2. The agitator was started and the vessel pressurized with N2 to 0.75 bar, then the pressure was released. This procedure was repeated 3 times, then the agitator was stopped before adding 0.225 g of 5% Pd/C. The agitator was started, the vessel pressurized with N2 to 0.75 bar, then the pressure was released. This procedure was repeated 3 times, then the agitator was stopped. The vessel was pressurized with H2 to 2 bar, then the pressure was released. This procedure was repeated 3 times, then the vessel was pressurized with H2 to 6.75 bar. The agitator was started and the suspension stirred until complete conversion was evident by HPLC. The H2 pressure was released, the vessel re-pressurized with N2 to 0.75 bar, then the pressure was released. This procedure was repeated 3 times then, the agitator was stopped, the reaction mixture filtered through celite and the filter cake rinsed with 30 ml EtOAc to give crude (S) -tetrahydrofuran-3-yl 3-aminobenzylcarbamate 2d as a solution in EtOAc that was used as is immediately in the next step.

Dissolved 17.6 g of Na2SO4 in 105 ml water at 200C in a separate container. Charged the EtOAc solution of aniline 2d and the aqueous solution of Na2SO4 into a 250 ml glass jacketed vessel purged with N2. The agitator was started to blend the phases and the mixture heated to 500C. Phenyl chloroformate (7.72 ml) was added dropwise to the solution over 1 hour while maintaining the temperature at 500C. The reaction was monitored by HPLC for consumption of 2d and phenyl chloroformate. Once the reaction was complete the agitator was stopped, the phases separated and the agitator restarted. Added 60 ml water at 500C, stirred the contents for 30 minutes at 500C, then stopped the agitator, separated the layers and restarted the agitator.

A mixture of 2c (50 g, 1.00 equivalent), 5% Pd/C (0.75 g, 50% water, 0.75 wt %) and isopropyl acetate (400 ml, 8 volumes) was added to a hydrogenation vessel under nitrogen and heated to 60 0C. The vessel was pressurized with hydrogen (1.00 bar overpressure) and the mixture stirred at 60 0C. The reaction was complete within 3 hours. The pressure was released and the vessel purged with nitrogen. The mixture was filtered through a pad of Celite® and then the hydrogenation vessel and pad were rinsed with isopropyl acetate (100 ml, 2 volumes) . The solution of 2d in isopropyl acetate was then combined with a solution of sodium sulfate (29.3 g, 1.10 equivalents) in water (150 ml, 3 vol) and then the mixture was heated to 70 0C. Phenyl chloroformate (25.7 ml, 1.10 equivalents) was then added to the mixture while maintaining a temp, of 70 0C. The reaction was stirred for 30 min after the end of addition and then the stirring was stopped. The phases were allowed to separate and the aqueous phase was removed. Water (150 ml, 3 vol) was then added and the mixture stirred for an additional 30 min before the stirring was stopped. The phases were allowed to separate and the aqueous phase removed. The mixture was then distilled at atmospheric pressure to azeotropically remove water from the organic phase. Compound 2β precipitated from solution when all of the water was removed. Distillation continued until there were 4 volumes of solvent remaining. The mixture was cooled to 20 0C over 5 hours then filtered to isolate the solid. The reactor and filter cake were washed with isopropyl acetate (2 vol) then the cake was dried under vacuum at 50 0C to afford 61. Ig (91%) of 2e. [0112] 3-metho2£y-4-(oxazol-5-yl)benzenainine (2g)

2f 2g

Added 10 g of 5- (2-methoxy-4-nitrophenyl) oxazole 2f to a 500 ml 3-neck flask then added 1.0 g of Nuchar SA.20 charcoal. Next added 200 ml of isopropyl acetate, heated the reaction vessel to 400C under nitrogen, stirred for 2 hours at 400C then heated to 800C and hot filtered to remove the charcoal. The filtrate was concentrated to 1/2 volume on a rotary evaporator before adding the solution to a 500 ml Parr bomb containing 600 mg of 5% Pd/C (50% wet) . The suspension was purged with nitrogen for 20 minutes, then the system was sealed the agitator started. The mixture was heated to 400C while continuing the flow of nitrogen, then the bomb was pressurized to 40 psi with hydrogen. The pressure was released, then the vessel re-pressurized with Hydrogen to 40 psi and the process repeated 3 more times. Finally, 40 psi of hydrogen was maintained until intermediate pressure chromatography showed a complete conversion to 3-methoxy-4- (oxazol-5-yl)benzenamine 2g.

Nitrogen was passed through the reaction, the mixture was cooled to room temperature, filtered through CeIite, rinsed with 20 ml of isopropyl acetate, then the filtrate volume reduced to 1/3 volume on a rotary evaporator under reduced pressure at 47°C. The mixture was cooled to room temperature, charged with 100 ml n-Heptane, the filtrate volume reduced to 1/3 on a rotary evaporator under reduced pressure at 47°C and this process was repeated one more time. The mixture was cooled to room temperature, filtered and dried at 45°C in a house vacuum oven to give 7.91 g of 3-methoxy-4- (oxazol-5- yl)benzenamine 2g (91% yield, 99.7% a/a) as a yellow solid with consistent 1H NMR (500 MHz, d6-DMSO) : 8.20 (s, IH); -7.32

[0115] Compound 2f (50 g, 1.0 eq. , Nippon Soda) and 1% Pt, 2% V on C (2.78 g, 64% wet, 2.0 wt % on a dry basis, Degussa Type CF1082) were charged to a hydrogenation vessel under nitrogen. Ethyl acetate (500 ml, 10 vol) was added and the mixture was heated to 60 0C. The vessel was pressurized with hydrogen (1.00 bar overpressure) and the mixture was stirred at 60 0C. The reaction was complete within 3 hours. The pressure was released and nitrogen was bubbled through the reaction mixture. The reaction mixture was filtered through Celite® and washed with EtOAc (100 ml, 2 vol) . The solvent level was reduced to 4 vol by distillation at reduced pressure and toluene (500 ml, 10 vol) was charged into the vessel. The solvent level was reduced to 4 vol by distillation at reduced pressure and a second portion of toluene (500 ml, 10 vol) was charged into the vessel. The solvent level was reduced to 5 vol under reduced pressure then the mixture was heated to 90 0C at atmospheric pressure to dissolve any solids. The solution was then cooled slowly to 20 0C to induce crystallization. The resulting yellow solid was filtered and washed with toluene (100 ml, 2 vol) to give compound 2g which was dried in a vacuum oven at 50 0C with a nitrogen bleed until a constant weight of 39.4 g (91%) was achieved.

Added 15 g of {3- [ ( (S) -tetrahydro-furan-3- yloxycarbonylamino) -methyl] -phenyl} -carbamic acid phenyl ester 2e and 8.58 g of 3-methoxy-4- (oxazol-5-yl)benzenamine 2g into a 500 ml 3-necked flask and then purged the system with nitrogen before adding 225 ml of ethyl acetate. Next added 5.43 g of diisopropylethylamine over 1 minute, then heated at reflux for 24 hours. Once the reaction was complete, the mixture was cooled to room temperature and stired for an additional 1 hour. Precipitated solid was filtered, washed with 45 ml of EtOAc 2 times, then dried at 58°C for 18 hours (until a LOD is achieved of less than 1%) to give 17.46 g of crude (S) -tetrahydrofuran-3-yl 3- (3- (3-methoxy-4- (oxazol-5- yl) phenyl) ureido)benzylcarbamate 2h (90.4% yield, 98.46% a/a) as a white crystalline solid.

Crude 2h was recrystallized in a 500 ml 3-neck flask by the following procedure. 15 g of 2h was dissolved in 84 ml of NMP and stirred for 10 minutes at 200C. The mixture was heated to 48°C, then MeOH (67.5 ml) was added dropwise over 20 minutes using a syringe pump and the mixture seeded with 0.15 g of crude 2h. The mixture was stirred at 480C for 10 minutes, during which time a thin slurry results. Additional MeOH (88.5 ml) was added dropwise using a syringe pump over 90 minutes at 48°C. After completed addition, the reactor was cooled to 00C over 5 hours and further stirred at 00C for 1 hour. The suspension was filtered, washed 2 times with MeOH (150 ml each) wherein each wash was stirred for 1 hour at ambient temperature and then pressed dry using nitrogen. The solid was dried at 500C in a house vacuum oven for 5 hours to give 11.7 g of

Added 2e (15 g, 1.0 eq) and 2g (8.58 g, 1.07 eq) into a jacketed reactor of suitable size before adding ethyl acetate (225 ml, 15 vol) and diisopropylethylamine (5.43 g, 1.0 eq) , then heated the mixture to reflux (75-85°C) for 24 hours. Once the reaction was complete, the mixture was cooled to room temperature and stired for an additional 1 hour. Precipitated solid was filtered, washed with EtOAc 2 times (45 ml, 3 vol each wash) , then dried at 580C for 18 hours (until a LOD is achieved of less than 1%) to give 17.46 g of crude 2h

(90.4% yield, 98.46% a/a) as a white crystalline solid. Crude 2h was recrystallized in a 500 ml 3-neck flask by the following procedure. 15 g of 2h was dissolved in 84 ml of NMP and stirred for 10 minutes at 200C. The mixture was heated to 48°C, then MeOH (67.5 ml) was added dropwise over 20 minutes using a syringe pump and the mixture seeded with 0.15 g of crude 2h. The mixture was stirred at 48°C for 10 minutes, during which time a thin slurry results. Additional MeOH (88.5 ml) was added dropwise using a syringe pump over 90 minutes at 48°C. After completed addition, the reactor was cooled to 00C over 5 hours and further stirred at 00C for 1 hour. The suspension was filtered, washed 2 times with MeOH (150 ml each) wherein each wash was stirred for 1 hour at ambient temperature and then pressed dry using nitrogen. The solid was dried at 500C in a house vacuum oven for 5 hours to give 11.7 g of S) -tetrahydrofuran-3-yl 3- (3- (3-methoxy-4- (oxazol-5-yl)phenyl)ureido)benzylcarbamate 2h (78% recovery, 99.93% a/a) as a white crystalline solid with consistent

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by Satish Singh

All product development scientists understand the importance of container closure to the sterility, stability, and delivery of a parenteral drug, including biotherapeutics. The glass vial remains a mainstay, while a number of biotherapeutics are targeting or becoming available in prefilled syringes. Subcutaneous (SC) administration is a desirable route of parenteral administration for biopharmaceuticals.

In 2010, Glenmark gained an exclusive worldwide license from Lay Line Genomics S.p.A. (Italy) for anti-TrkA antibodies and their entire intellectual property portfolio in the TrkA field. GBR 900 is the optimized anti-TrkA antibody emerging from this exclusive worldwide license.

April 28, 2014
GlaxoSmithKline (GSK) and Medicines for Malaria Venture (MMV) announced the start of a Phase 3 global program to evaluate the efficacy and safety of tafenoquine, an investigational medicine which is being developed for the treatment and relapse prevention (radical cure) of Plasmodium vivax (P. vivax) malaria.

P. vivax malaria, a form of the disease caused by one of several species of Plasmodium parasites known to infect humans, occurs primarily in South and South East Asia, Latin America and the horn of Africa. Severe anemia, malnutrition and respiratory distress are among the most serious consequences described to be caused by the infection.

The Phase 3 program includes two randomized, double-blind treatment studies to investigate tafenoquine in adult patients with P. vivax malaria. The DETECTIVE study (TAF112582) aims to evaluate the efficacy, safety and tolerability of tafenoquine as a radical cure for P. vivax malaria, co-administered with chloroquine, a blood stage anti-malarial treatment. The GATHER study (TAF116564) aims to assess the incidence of hemolysis and safety and efficacy of tafenoquine compared to primaquine, the only approved treatment currently available for the radical cure of P. vivax malaria.

Tafenoquine is not yet approved or licensed for use anywhere in the world.

“P. vivax malaria can affect people of all ages and is particularly insidious because it has the potential to remain dormant within the body in excess of a year, and causes some patients to experience repeated episodes of illness after the first mosquito bite,” said Nicholas Cammack, head, Tres Cantos Medicines Development Center for Diseases of the Developing World. “Our investigation of tafenoquine for the treatment of P. vivax malaria is part of GSK’s efforts to tackle the global burden of malaria. Working with our partners, including MMV, we are determined to stop malaria in all its forms.”

“One of the big challenges we face in tackling malaria is to have new medicines to prevent relapse, caused by dormant forms of P. vivax,” said Dr. Timothy Wells, MMV’s chief scientific officer. “The Phase 3 program is designed to build upon the promising results of the Phase 2b study which showed that treatment with tafenoquine prevented relapses. If successful, tafenoquine has the potential to become a major contributor to malaria elimination. It’s a great privilege to be working with GSK on this project; they have a clear commitment to changing the face of public health in the countries in which we are working.”

The proposed indication for tafenoquine is for treatment of the hypnozoite stages of Plasmodium vivax (and also Plasmodium ovale) that are responsible for relapse of these malaria species even when the blood stages are successfully cleared. This is only now achieved by administration of daily primaquine for 14 days. The main advantage of tafenoquine is that it has a long half-life (2–3 weeks) and therefore a single treatment may be sufficient to clear hypnozoites. The shorter regimen has been described as an advantage.[3]

Like primaquine, tafenoquine causes haemolysis in people with G-6-P deficiency.[1] Indeed the long half-life of tafenoquine suggests that particular care should be taken to ensure that individuals with severe deficiency do not receive the drug.

The dose of tafenoquine has not been firmly established, but for the treatment of Plasmodium vivax malaria, a dose of 800 mg over three days has been used.[4]

Synonyms

Nitration of 1,2-dimethoxybenzene (XXIX) with HNO3/AcOH gives 4,5-dimethoxy-1,2-dinitrobenzene (XXX), which is treated with ammonia in hot methanol to yield 4,5-dimethoxy-2-nitroaniline (XXXI). Cyclization of compound (XXXI) with buten-2-one (XXXII) by means of H3PO4 and H3AsO4 affords 5,6-dimethoxy-4-methyl-8-nitroquinoline (XXXIII), which is selectively mono-demethylated by means of HCl in ethanol to provide 5-hydroxy-6-methoxy-4-methyl-8-nitroquinoline (XXXIV). Reaction of quinoline (XXXIV) with POCl3 gives the corresponding 5-chloro derivative (XXXV), which is condensed with 3-(trifluoromethyl)phenol (IV) by means of KOH to yield the diaryl ether (XXXVI). Finally, the nitro group of (XXXVI) is reduced by means of H2 over PtO2 in THF or H2 over Raney nickel.

Nitration of 2-fluoroanisole (XXXVII) with HNO3/Ac2O gives 3-fluoro-4-methoxynitrobenzene (XXXVIII), which is reduced to the corresponding aniline (XXXIX) with SnCl2/HCl. Reaction of compound (XXXIX) with Ac2O yields the acetanilide (XL), which is nitrated with HNO3 to afford 5-fluoro-4-methoxy-2-nitroacetanilide (XLI). Hydrolysis of (XLI) with NaOH provides 5-fluoro-4-methoxy-2-nitroaniline (XLII), which is cyclized with buten-2-one (XXXII) by means of As2O5 and H3PO4 to furnish 5-fluoro-6-methoxy-4-methyl-8-nitroquinoline (XLIII). Condensation of quinoline (XLIII) with 3-(trifluoromethyl)phenol (IV) by means of K2CO3 gives the diaryl ether (XXXIV), which is finally reduced by means of H2 over PtO2 in THF.

………………..

US 4617394

Reaction of 8-amino-6-methoxy-4-methyl-5-[3-(trifluoromethyl)phenoxy]quinoline (XIV) with phthalic anhydride (XV) affords the phthalimido derivative (XVI), which is oxidized with MCPBA to yield the quinoline N-oxide (XVII). Treatment of compound (XVII) with neutral alumina gives the quinolone derivative (XVIII), which by reaction with POCl3 in refluxing CHCl3 provides the 2-chloroquinoline derivative (XIX). Alternatively, reaction of the quinoline N-oxide (XVII) with POCl3 as before also gives the 2-chloroquinoline derivative (XIX) The removal of the phthalimido group of compound (XIX) by means of hydrazine in refluxing ethanol gives the chlorinated aminoquinoline (XX), which is finally treated with MeONa in hot DMF.

……………….

US 6479660; WO 9713753

Chlorination of 6-methoxy-4-methylquinolin-2(1H)-one (I) with SO2Cl2 in hot acetic acid gives the 5-chloro derivative (II), which is nitrated with HNO3 in H2SO4 to yield the 8-nitroquinolinone (III). Condensation of compound (III) with 3-(trifluoromethyl)phenol (IV) by means of KOH in NMP provides the diaryl ether (V), which is treated with refluxing POCl3 to afford the 2-chloroquinoline (VI). Reaction of compound (VI) with MeONa in refluxing methanol results in the 2,6-dimethoxyquinoline derivative (VII), which is reduced with hydrazine over Pd/C to give the 8-aminoquinoline derivative (VIII). Condensation of aminoquinoline (VIII) with N-(4-iodopentyl)phthalimide (IX) by means of diisopropylamine in hot NMP yields the phthalimido precursor (X), which is finally cleaved with hydrazine in refluxing ethanol.

Reaction of 1,4-dibromopentane (XI) with potassium phthalimide (XII) gives N-(4-bromopentyl)phthalimide (XIII), which is then treated with NaI in refluxing acetone.

Reaction of 4-methoxyaniline (XXI) with ethyl acetoacetate (XXII) by means of triethanolamine in refluxing xylene gives the acetoacetanilide (XXIII), which is cyclized by means of hot triethanolamine and H2SO4 to yield 6-methoxy-4-methylquinolin-2(1H)-one (I), which is treated with refluxing POCl3 to provide 2-chloro-6-methoxy-4-methylquinoline (XXIV). Reaction of compound (XXIV) with SO2Cl2 in hot AcOH affords 2,5-dichloro-6-methoxy-4-methylquinoline (XXV), which is treated with MeONa in refluxing methanol to furnish 5-chloro-2,6-dimethoxy-4-methylquinoline (XXVI). Alternatively, the reaction of compound (XXIV) with MeONa as before gives 2,6-dimethoxy-4-methylquinoline (XXVII), which is treated with SO2Cl2 in hot AcOH to give the already described 5-chloro-2,6-dimethoxy-4-methylquinoline (XXVI). Nitration of compound (XXVI) with KNO3 and P2O5 gives the 8-nitroquinoline derivative (XXVIII), which is condensed with 3-(trifluoromethyl)phenol (IV) by means of KOH in hot NMP to yield the diaryl ether (VII). Finally, the nitro group of compound (VII) is reduced with hydrazine over Pd/C.

//////////////////////

J Med Chem 1989,32(8),1728-32

Synthesis of the intermediate diazepinone (IV) is accomplished by a one-pot synthesis. Condensation of 2-chloro-3-aminopyridine (I) with the anthranilic ester (II) is effected in the presence of potassium tert-butoxide as a catalyst. The resulting anthranilic amide (III) is cyclized under the influence of catalytic amounts of sulfuric acid. Treatment of (IV) with chloroacetylchloride in toluene yields the corresponding choroacetamide (V). The side chain of AQ-RA 741 is prepared starting from 4-picoline, which is alkylated by reaction with 3-(diethylamino)propylchloride in the presence of n-butyllithium. Hydrogenation of (VIII) using platinum dioxide as a catalyst furnishes the diamine (IX), which is coupled with (V) in the presence of catalytic amounts of sodium iodide in acetone leading to AQ-RA 741 as its free base.

LDK378 is a highly selective inhibitor of an important cancer target, anaplastic lymphoma kinase (ALK)

Ceritinib (LDK378) a selective inhibitor of the cancer target anaplastic lymphoma kinase (ALK), shows a marked clinical response in patients with ALK+ non-small cell lung cancer (NSCLC) during the 49th Annual Meeting of the American Society of Clinical Oncology (ASCO) on June 3, 2013. FDA designated LDK378 as Breakthrough Therapy in March, 2013. A regulatory application was submitted in January 2014 in the US for LDK378 (ceritinib). see current status………….

April 29, 2014

Acting 4 months ahead of schedule, the FDA has granted an accelerated approval to ceritinib (Zykadia; LDK378) as a treatment for patients with ALK-positive metastatic non-small cell lung cancer (NSCLC) following treatment with crizotinib (Xalkori), based on a single-arm clinical trial demonstrating a durable improvement in overall response rates (ORR).

The approval for the second-generation ALK inhibitor was supported by results from an analysis of 163 patients treated with single-agent ceritinib at 750 mg daily following progression on crizotinib. In these select patients, the ORR was 54.6% with a 7.4-month median duration of response, according to data submitted to the FDA by Novartis, the company developing the drug. Based on these findings, the FDA granted ceritinib a Breakthrough Therapy designation, Priority Review, and orphan product designation.

“Today’s approval illustrates how a greater understanding of the underlying molecular pathways of a disease can lead to the development of specific therapies aimed at these pathways,” Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in a statement. “It also demonstrates the FDA’s commitment to working cooperatively with companies to expedite a drug’s development, review and approval, reflecting the promise of the breakthrough therapy designation program.”

In the study that was the basis for the approval, the primary endpoint was ORR by RECIST criteria with a secondary outcome measure of duration of response. Treatment with ceritinib resulted in an ORR of 54.6% by investigator assessment with a median duration of response of 7.4 months. By blinded independent central review, the ORR was 43.6% and the duration of response was 7.1 months.

Earlier this year, results from a dose escalation study that examined ceritinib in 130 patients who were untreated or refractory to crizotinib were published in the New England Journal of Medicine. In this analysis for patients who received doses of at least 400 mg (n = 114), the ORR was 58%. Patients who had progressed on crizotinib (n = 80) experienced an ORR of 56% and those who were crizotinib-naïve (n =34) had an ORR of 62%.The median progression-free survival was 7.0 months and the median duration of response was 8.2 months (95% CI; 6.9-11.4). Additionally, responses were seen in patients with untreated metastatic brain lesions who progressed on prior therapy with crizotinib, the authors of the study noted.

The most frequent adverse events were nausea (82%), diarrhea (75%), vomiting (65%), fatigue (47%) and increased alanine aminotransferase levels (35%). These adverse events were generally mild and resolved when treatment stopped or the dose was reduced.

The most common grade 3 or 4 drug-related adverse events were increased alanine aminotransferase levels (21%), increased aspartate aminotransferase levels (11%), diarrhea (7%) and increased lipase levels (7%), all of which were reversible upon treatment discontinuation.

“Zykadia represents an important treatment option for ALK-positive NSCLC patients who relapse after starting initial therapy with crizotinib,” Alice Shaw, MD, PhD, of the Massachusetts General Hospital (MGH) Cancer Center, lead author of the report, said in a statement. “This approval will affect the way we manage and monitor patients with this type of lung cancer, as we will now be able to offer them the opportunity for continued treatment response with a new ALK inhibitor.”Two phase III studies are enrolling patients to further explore the efficacy and safety of ceritinib in patients with ALK-positive NSCLC. These studies will likely act as confirmation for the accelerated approval. In the first, ceritinib will be compared with chemotherapy in untreated patients with ALK-rearranged NSCLC (NCT01828099). The second will compare ceritinib to chemotherapy in ALK-positive patients with NSCLC following progression on chemotherapy and crizotinib (NCT01828112).

“The approval of Zykadia less than three and a half years after the first patient entered our clinical trial exemplifies what is possible with a highly focused approach to drug development and strong collaboration,” Alessandro Riva, MD, president of Novartis Oncology ad interim and global head of Oncology Development and Medical Affairs, said in a statement. “The dedication of clinical investigators, patients, the FDA and others has enabled us to bring this medicine to patients in need as swiftly as possible.”

Nitration of 2-chloro-4-fluoro-1-methylbenzene with KNO3 in the presence of H2SO4 gives 1-chloro-5-fluoro-2-methyl-4-nitrobenzene , which upon condensation with isopropyl alcohol in the presence of Cs2CO3 in 2-PrOH at 60 °C yields 5-isopropoxy-2-methyl-4-nitrobenzene .

Suzuki coupling of chloride with 4-pyridineboronic acid in the presence of Pd2dba3, K3PO4 and SPhos in dioxane/water at 150 °C (microwave irradiation) provides 4-(5-isopropoxy-2-methyl-4-nitrophenyl)pyridine , which is then subjected to global reduction using H2 over PtO2 in the presence of TFA in AcOH to afford 2-isopropoxy-5-methyl-4-piperidin-4-ylaniline .

N-Protection of piperidine with Boc2O in the presence of Et3N in CH2Cl2 furnishes the corresponding carbamate (VIII), which upon Buchwald-Hartwig cross coupling with 2,5-dichloropyrimidine derivative (prepared by condensation of 2-(isopropylsulfonyl)aniline and 2,4,5-trichloropyrimidine in the presence of NaH in DMSO/DMF) in the presence of Pd(OAc)2, Xantphos and Cs2CO3 in THF affords Boc-protected ceritinib . Finally, removal of Boc-group in compound using TFA in CH2Cl2 furnishes the target compound ceritinib

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Anaplastic lymphoma kinase (ALK), a member of the insulin receptor superfamily of receptor tyrosine kinases, has been implicated in oncogenesis in hematopoietic and non- hematopoietic tumors. The aberrant expression of full-length ALK receptor proteins has been reported in neuroblastomas and glioblastomas; and ALK fusion proteins have occurred in anaplastic large cell lymphoma. The study of ALK fusion proteins has also raised the possibility of new therapeutic treatments for patients with ALK-positive malignancies. (Pulford et al., Cell. MoI. Life Sci. 61:2939-2953 (2004)).

Focal Adhesion Kinase (FAK) is a key enzyme in the integrin-mediated outside-in signal cascade (D. Schlaepfer et al., Prog Biophys MoI Biol 1999, 71, 43578). The trigger in the signal transduction cascade is the autophosphorylation of Y397. Phosphorylated Y397 is a SH2 docking site for Src family tyrosine kinases; the bound c-Src kinase phosphorylates other tyrosine residues in FAK. Among them, phsophorylated Y925 becomes a binding site for the SH2 site of Grb2 small adaptor protein. This direct binding of Grb2 to FAK is one of the key steps for the activation of down stream targets such as the Ras-ERK2/MAP kinase cascade.

Zeta-chain-associated protein kinase 70 (ZAP-70), a member of the protein tyrosine kinase family, is of potential prognostic importance in chronic lymphocytic leukemia (CLL). ZAP-70, known to be of importance in T and NK cell signaling but absent in normal peripheral B cells, is expressed in the majority of the poorer prognosis unmutated CLL and absent in most cases with mutated IgVH genes. ZAP-70 is also expressed in a minority of other B cell tumors. (Orchard et al., Leuk. Lymphoma 46:1689-98 (2005)). [0006] Insulin- like growth factor (IGF-I) signaling is highly implicated in cancer, with the IGF-I receptor (IGF-IR) as the predominating factor. IGR-IR is important for tumor transformation and survival of malignant cells, but is only partially involved in normal cell growth. Targeting of IGF-IR has been suggested to be a promising option for cancer therapy. (Larsson et al., Br. J. Cancer 92:2097-2101 (2005)).

Because of the emerging disease-related roles of ALK, FAK, ZAP-70 and IGF-IR, there is a continuing need for compounds which may be useful for treating and preventing a disease which responds to inhibition of ALK, FAK, ZAP-70 and/or IGF-IR

The compound 5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2- (propane-2-sulfonyl)-phenyl]-pyrimidine-2, 4-diamine, in the form of a free base, of formula

(I)

is an anaplastic lymphoma kinase (ALK) inhibitor, a member of the insulin receptor super family of receptor tyrosine kinases. Compound I was originally described in WO 2008/073687 Al as Example 7, compound 66. WO 2008/073687 Al , however, provides no information about crystalline forms of 5-

combination thereof. The crystalline forms exhibit new physical properties that may be exploited in order to obtain new pharmacological properties, and that may be utilized in the drug product development of 5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2- (propane-2-sulfonyl)-phenyl]-pyrimidine-2, 4-diamine.

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Depiction of simulated potassium channel and surrounding environment. Potassium ions (green) are unable to pass through because water molecules (red and white) are present inside the protein, locking the channel into an inactivated state. Credit: Benoit Roux, University of Chicago

Just 12 molecules of water cause the long post-activation recovery period required by potassium ion channels before they can function again. Using molecular simulations that modeled a potassium channel and its immediate cellular environment, atom for atom, University of Chicago scientists have revealed this new mechanism in the function of a nearly universal biological structure, with implications ranging from fundamental biology to the design of pharmaceuticals. Their findings were published online July 28 in Nature.

“Our research clarifies the nature of this previously mysterious inactivation state. This gives us better understanding of fundamental biology and should improve the rational design of drugs, which often target the inactivated state of…

AZD8926 is a potent glycogen synthase kinase-3β (GSK3β) inhibitor which has potential for treating several CNS disorders, such as Alzheimer’s disease (AD), schizophrenia, and chronic as well as acute neurodegenerative diseases

…………………..

Development of a new, safe, and scalable route to the GSK3β inhibitor, AZD8926, is presented.

In brief, the process constitutes of (i) a synthesis of 1-(pyran-4-yl)-2-trifluoromethyl-imidazole, 14; (ii) a Ziegler-type coupling of lithiated 14 with commercially available 2-chloro-5-fluoropyrimidine via 1,2-addition over the 3,4-C–N bond; (iii) a copper-catalyzed dehydrogenative aromatization using oxygen as the stoichiometric oxidant; and (iv) an aromatic C–N bond formation using either a Buchwald–Hartwig coupling or an acid-catalyzed amination. This process circumvents the main issue in the early-phase route, in which serious process safety constraints were associated with the hazardous properties of the structure, formation, and reduction of 5-methyl-4-nitroisoxazole, 2 (4200 J/g). The new process has been demonstrated on a multigram, 2-L scale. The overall yield was improved from 4 to 14%, and the number of steps decreased from 12 to 10

The butyl acid (112.6 g, 0.24 mol) was mixed in THF (675 mL) at 25 °C. N-Methyl-piperazine (29.3 mL, 0.26 mol), NMM (41 mL, 0.37 mol), and HOBt as a water solution (17 mL, 24.4 mmol, 19.4%) were added to the reaction solution. EDCI (72.7 g, 0.34 mol) dissolved in water (220 mL) was added over 10 min. The reaction mixture was heated at 45 °C for 1 h. EtOAc (675 mL) was added, and the reaction solution was heated at 55 °C. The lower water phase was separated off, and the organic phase was washed with 5% NaCl in water (225 mL), and then the organic solution was left stirring at 55 °C. Heptane (675 mL) was added over 1.5 h to initiate crystallization. The slurry was cooled to 5 °C over 8 h and left for at least 2 h. The solids were collected, washed with a cooled mixture of EtOAc and heptane (1:1, 600 mL), and dried at 60 °C with vacuum to give compound 9 (120.8 g, 89% yield, corrected for 96.1 wt % 1H NMR assay) as a light-yellow solid.

Anilines of formula (III) are commercially available compounds, or they are known in the literature, or they are prepared by standard processes known in the art.

Process b). Compounds of formula (IV) and amines of formula (V) may be reacted together under standard Buchwald conditions as described in Process a.

A synthesis of pyrimidines of formula (IV) is described in Scheme 2(RX may be the same or different and is Q.βalkytyT should not be there

Scheme 2

Compounds of formula (V) are commercially available compounds, or they are known in the literature, or they are prepared by standard processes known in the art.

Compounds of formula (VI) in which R6 has the general structure Ra-CH-Rb (wherein Ra and Rb are as defined in formula I and Rx may be the same or different and is C1-6alkyl) and R9 is F may be prepared according to Scheme 3

The title compound was prepared in accordance with the general method B with the exception that guanidine carbonate was used. Using (2Z)-3-dimethylamino-2-fluoro-l-[l- (tetrahydro-2H-pyran-4-yl)-2-trifluoromethyl- lH-imidazol-5 -y l]prop-2-en- 1 -one (0.330 g, 1.0 mmol, obtained from Example 34(c)) and guanidine carbonate (0.45 g, 2.50 mmol). After purification by flash chromatography (heptane/EtOAc 1 :2), the title compound was obtained (0.170 g, 51 %) as a white solid.

WO 2011/131103 A1 discloses a formula including the inner (I) compound smile lactone derivative or a salt thereof a pharmaceutical composition, preparation and use for the preparation of anticancer drugs.But no problem about the compound of formula polymorph (I), have not been reported for formula (I) compounds of the crystalline areas.The present invention provides compounds of formula (I) dimethylamine smile lactone crystalline fumarate and its preparation method.

An object of the present invention to provide a compound of formula (I) a lactone compound smile dimethylamine i.e. crystalline fumarate polymorph A.Another object of the present invention to provide a method for preparing crystalline compound of formula (I).A lactone compound of dimethylamine fumaric polymorph A boat characteristics of formula (I):

A new crystalline form of sphaelactone dimethylamine fumarate and its preparation are claimed. The parent compound is ACT-001 (DMAMCL) which Accenda Tech and Nankai University are investigating for potential oral treatment of acute leukemia. Preclinical studies were completed in October 2012, and an application for clinical trials was planned for 2013. Picks up from WO2013163936, which claims preparation of similar compounds.

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In a new study in patients with osteoarthritis (OA) of the knee, at 12 months, total femorotibial cartilage thickness loss was reduced in sprifermin (recombinant human fibroblast growth factor 18)-treated knees compared to placebo-treated knees, with effects being significant in the lateral femorotibial compartment but not in the central femorotibial compartment.

Results published in Arthritis & Rheumatology, a journal of the American College of Rheumatology (ACR), showed that sprifermin dosed at 100µg reduced loss of cartilage thickness and volume in the total femorotibial joint and in the lateral knee compartment (outside of the knee).

The 2010 Global Burden of Disease Study estimates that OA affects 150 million people around the world, with the ACR reporting 27 million Americans over 25 years of age diagnosed with the disease. While OA is the most common cause of physical disability in older adults, studies suggest that the average age at diagnosis is…

WO-2014059203 describes Crystalline forms of (S,E)-4-(2-(3-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acryloyl)-5-(4-methyl-2-oxopiperazin-1-yl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamido) benzoic acid, and their use for treating thromboembolic disorders eg unstable angina or acute coronary syndrome, are claimed. This compound appears to have emerged as a lead from the factor XIa antagonists claimed in WO2013056060. This compound may be the parenteral factor XIa inhibitor or the oral factor XIa inhibitor which were being investigated by BMS. However both programs were no longer listed on the company website in February 2014. The concurrently published WO2014059202 and ‘214 claim similar compounds.

CRYSTALLINE FORMS OF A FACTOR XIA INHIBITOR (Fri, 18 Apr 2014) The instant invention provides crystalline forms of (S,E)-4-(2-(3-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acryloyl)-5-(4-methyl-2-oxopiperazin-1-yl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamido)benzoic acid and its solvates thereof; processes for the production of such crystalline forms; pharmaceutical compositions comprising such crystalline forms; and methods of treating thromboembolic disorders with such crystalline forms or such pharmaceutical compositions. >> read more

[00223] Scheme 2 describes an alternative method to access compounds of this invention. Reaction of acid le, isocyanide 2a, and imine 2b can give Ugi product 2d (Schuster, I. et al, Letters in Organic Chemistry, 4(2): 102-108 (2007)). Selective oxidation of tetrahydroisoquinoline 2c using known methods such as Mn02 (Aoyama, T. et al, Synlett, 1 :35-36 (1998)) can yield imine 2b, which can then be used via the three component Ugi coupling procedures described above. The Ugi coupling procedures can be used extensively with other imino derived intermediates contained in this invention. Further manipulations of the Ugi derived products can afford compounds of this invention.

[00225] Preparation of substituted THQ analogs is shown in Scheme 4. Bromide 4a can be converted to nitrile 4b under lithiation conditions. Hydrolysis under basic conditions should lead to acid 4c, which can be converted to carbamate 4e via Curtius rearrangement. Formation of the THQ intermediate 4f can then be accomplished by treatment with paraformaldehyde in a mixture of acetic and sulfuric acid (Bigge, C. F. et al, Bioorganic & Medicinal Chemistry Letters, 3(1): 39-42 (1993)). Deprotection of carbamate 4f followed by protection with B0C2O should afford intermediate 4h, which can be subjected to the Suzuki cross coupling reaction with an appropriate boronate or boronic acid or the Stille coupling procedures known to those in the art.